Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many patients with malignancies as well as other life-threatening conditions such as primary immunodeficiency disorders (PID). Chronic norovirus infection is a potential complication of HSCT, and can cause chronic diarrhea and wasting. There are currently no available therapies to treat norovirus. We have demonstrated that healthy individuals have T cell immunity against norovirus, and that viral epitopes in antigens NS6 and VP1 are well conserved across viral genotypes. The overarching goal of this proposal is the development of a novel treatment for chronic norovirus infection in patients undergoing HSCT. In our previous study, we demonstrated safety and potential efficacy of virus-specific T cells targeting CMV, EBV, and adenovirus as well as the feasibility of this approach. To restore immunity against norovirus we now propose to take blood from the healthy donors and expand and enrich the norovirus-specific T cells (NSTs) present in donors' blood, followed by extensive characterization of the function of NSTs. We will then give NSTs as treatment for chronic norovirus in patients who have undergone HSCT. If successful, this novel antiviral therapy could provide long-term protection against norovirus. Thus, we hypothesize that the infusion of NSTs will be safe and effective against norovirus infections in patients post HSCT, and will restore lasting immunity against norovirus. We further hypothesize that antiviral efficacy will correlate with expansion of T cells recognizing immunodominant viral epitopes, which will correspond to stable regions of the viral genome. Through this phase I IND study, we will address the following specific aims: 1) To determine the breadth of norovirus T cell epitopes and MHC restrictions, as well as their genetic stability in clinical viral isolates, 2) To study the safety and feasibility of administering ex vivo expanded T cells targeting norovirus as treatment of chronic infection in immunocompromised patients, and 3) To determine whether infusion of NSTs can enhance norovirus specific immunity in immune compromised hosts. Collectively, these aims will determine if NSTs may be a safe and effective treatment for chronic norovirus infection in patients post HSCT. Completion of this study could provide a novel antiviral therapy which could reduce virus- associated morbidity in HSCT, and will guide future cellular therapy and vaccine trials targeting enteric viruses.